Project Summary: The goal of this proposal is to evaluate the hypothesis that genetic polymorphisms play a significant role in the development of cognitive changes following chemotherapy. Specifically, the primary objective of this proposal is to characterize the role of polymorphisms in genes which modulate: 1) the degree of exposure to chemotherapeutic agents (e.g., blood brain barrier transporter systems), 2) neural plasticity/repair in response to CMS injury, and 3) maintenance and regulation of cognitive processes (central catecholaminergic and cholinergic systems) in determining the risk of developing cognitive deficits after chemotherapy, and the severity of these deficits. We hypothesize that alleles which functionally reduce efficiency of blood brain barrier efflux pumps and/or reduce neural repair/plasticity and/or central catecholaminergic/ cholinergic tone increase risk for chemotherapy-induced cognitive decline. Further, due to additive and possibly synergistic effects, the overall number of alleles reducing catecholaminergic/cholinergic tone, repair/plasticity, or efflux pump efficiency will serve as a useful index in predicting the degree of cognitive impairment. The research strategy for this proposal is to utilize stored DMA from two cohorts of cancer survivors who have been / will be well characterized in terms of neuropsychological functioning, treatment (chemotherapy vs. local therapy), and medical / demographic characteristics: 1) 10-year cancer survivors evaluated in a cross-sectional study who were treated with adjuvant chemotherapy or local therapy and 2) early stage breast cancer and lymphoma patients who are participating in two NCI funded (CA87845, CA101318) longitudinal studies in which patients treated with chemotherapy or local therapy are being evaluated with neuropsychological tests at pre-treatment and 1, 6, and 18 months post-treatment. Relevance: Identification of genes associated with chemotherapy-induced cognitive changes has important implications for understanding the mechanism by which chemotherapy can cause cognitive changes and for the development of treatments targeted to the biological systems influenced by those genes. [unreadable] [unreadable] [unreadable]